Selective Ablation of Tumorigenic Cells Following Human Induced Pluripotent Stem Cell‐Derived Neural Stem/Progenitor Cell Transplantation in Spinal Cord Injury

Tumorigenesis is an important problem that needs to be addressed in the field of human stem/progenitor cell transplantation for the treatment of subacute spinal cord injury (SCI). When certain “tumorigenic” cell lines are transplanted into the spinal cord of SCI mice model, there is initial improvem...

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Published inStem cells translational medicine Vol. 8; no. 3; pp. 260 - 270
Main Authors Kojima, Kota, Miyoshi, Hiroyuki, Nagoshi, Narihito, Kohyama, Jun, Itakura, Go, Kawabata, Soya, Ozaki, Masahiro, Iida, Tsuyoshi, Sugai, Keiko, Ito, Shuhei, Fukuzawa, Ryuji, Yasutake, Kaori, Renault‐Mihara, Francois, Shibata, Shinsuke, Matsumoto, Morio, Nakamura, Masaya, Okano, Hideyuki
Format Journal Article
LanguageEnglish
Published Hoboken, USA John Wiley & Sons, Inc 01.03.2019
Oxford University Press
Subjects
Ablation
Animals
Apoptosis
Carcinogenesis - pathology
Cell cycle
Cell Differentiation - physiology
Cells, Cultured
Cytotoxicity
Diabetes mellitus
Disease Models, Animal
Enabling Technologies for Cell‐Based Clinical Translation
Female
Genes
Herpes simplex
Herpes simplex virus thymidine kinase
Herpes viruses
Human induced pluripotent stem cell‐derived neural stem/progenitor cell
Humans
Induced Pluripotent Stem Cells - cytology
Medical research
Mice
Mice, Inbred NOD
Mice, SCID
Neural stem cells
Neural Stem Cells - cytology
Neurons - physiology
Pharmaceutical industry
Pluripotency
Progenitor cells
Recovery of Function - physiology
Scientific equipment and supplies industry
Spinal Cord - physiology
Spinal cord injuries
Spinal Cord Injuries - therapy
Spinal cord injury
Stem cell research
Stem cell therapy
Stem cell transplantation
Stem Cell Transplantation - methods
Stem cells
Suicide
Suicide gene
Suicide genes
Tetracycline
Tetracyclines
Thymidine
Thymidine kinase
Transplantation
Tumorigenesis
Tumors
United States
Japan
Germany
Human induced pluripotent stem cell-derived neural stem/progenitor cell
Stem cell therapy
Spinal cord injury
Suicide gene
Herpes simplex virus thymidine kinase
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Abstract Tumorigenesis is an important problem that needs to be addressed in the field of human stem/progenitor cell transplantation for the treatment of subacute spinal cord injury (SCI). When certain “tumorigenic” cell lines are transplanted into the spinal cord of SCI mice model, there is initial improvement of motor function, followed by abrupt deterioration secondary to the effect of tumor growth. A significant proportion of the transplanted cells remains undifferentiated after transplantation and is thought to increase the risk of tumorigenesis. In this study, using lentiviral vectors, we introduced the herpes simplex virus type 1 thymidine kinase (HSVtk) gene into a human induced pluripotent stem cell‐derived neural stem/progenitor cell (hiPSC‐NS/PC) line that is known to undergo tumorigenic transformation. Such approach enables selective ablation of the immature proliferating cells and thereby prevents subsequent tumor formation. In vitro, the HSVtk system successfully ablated the immature proliferative neural cells while preserving mature postmitotic neuronal cells. Similar results were observed in vivo following transplantation into the injured spinal cords of immune‐deficient (nonobese diabetic–severe combined immune‐deficient) mice. Ablation of the proliferating cells exerted a protective effect on the motor function which was regained after transplantation, simultaneously defending the spinal cord from the harmful tumor growth. These results suggest a potentially promising role of suicide genes in opposing tumorigenesis during stem cell therapy. This system allows both preventing and treating tumorigenesis following hiPSC‐NS/PC transplantation without sacrificing the improved motor function. Stem Cells Translational Medicine 2019;8:260&270 The herpes simplex virus thymidine kinase (HSVtk) gene was introduced into a tumorigenic cell line of human induced pluripotent stem cell‐derived neural stem/progenitor cells (hiPSC‐NS/PCs) prior to transplantation into spinal cord injury mouse models. Administration of ganciclovir (GCV) following transplantation successfully ablated the immature tumorigenic cells while preserving the mature neuronal cells and the improved motor function.
AbstractList Tumorigenesis is an important problem that needs to be addressed in the field of human stem/progenitor cell transplantation for the treatment of subacute spinal cord injury (SCI). When certain "tumorigenic" cell lines are transplanted into the spinal cord of SCI mice model, there is initial improvement of motor function, followed by abrupt deterioration secondary to the effect of tumor growth. A significant proportion of the transplanted cells remains undifferentiated after transplantation and is thought to increase the risk of tumorigenesis. In this study, using lentiviral vectors, we introduced the herpes simplex virus type 1 thymidine kinase (HSVtk) gene into a human induced pluripotent stem cell-derived neural stem/progenitor cell (hiPSC-NS/PC) line that is known to undergo tumorigenic transformation. Such approach enables selective ablation of the immature proliferating cells and thereby prevents subsequent tumor formation. In vitro, the HSVtk system successfully ablated the immature proliferative neural cells while preserving mature postmitotic neuronal cells. Similar results were observed in vivo following transplantation into the injured spinal cords of immune-deficient (nonobese diabetic-severe combined immune-deficient) mice. Ablation of the proliferating cells exerted a protective effect on the motor function which was regained after transplantation, simultaneously defending the spinal cord from the harmful tumor growth. These results suggest a potentially promising role of suicide genes in opposing tumorigenesis during stem cell therapy. This system allows both preventing and treating tumorigenesis following hiPSC-NS/PC transplantation without sacrificing the improved motor function. Stem Cells Translational Medicine 2019;8:260&270
Tumorigenesis is an important problem that needs to be addressed in the field of human stem/progenitor cell transplantation for the treatment of subacute spinal cord injury (SCI). When certain "tumorigenic" cell lines are transplanted into the spinal cord of SCI mice model, there is initial improvement of motor function, followed by abrupt deterioration secondary to the effect of tumor growth. A significant proportion of the transplanted cells remains undifferentiated after transplantation and is thought to increase the risk of tumorigenesis. In this study, using lentiviral vectors, we introduced the herpes simplex virus type 1 thymidine kinase (HSVtk) gene into a human induced pluripotent stem cell-derived neural stem/progenitor cell (hiPSC-NS/PC) line that is known to undergo tumorigenic transformation. Such approach enables selective ablation of the immature proliferating cells and thereby prevents subsequent tumor formation. In vitro, the HSVtk system successfully ablated the immature proliferative neural cells while preserving mature postmitotic neuronal cells. Similar results were observed in vivo following transplantation into the injured spinal cords of immune-deficient (nonobese diabetic-severe combined immune-deficient) mice. Ablation of the proliferating cells exerted a protective effect on the motor function which was regained after transplantation, simultaneously defending the spinal cord from the harmful tumor growth. These results suggest a potentially promising role of suicide genes in opposing tumorigenesis during stem cell therapy. This system allows both preventing and treating tumorigenesis following hiPSC-NS/PC transplantation without sacrificing the improved motor function. Stem Cells Translational Medicine 2019;8:260&270.
Tumorigenesis is an important problem that needs to be addressed in the field of human stem/progenitor cell transplantation for the treatment of subacute spinal cord injury (SCI). When certain “tumorigenic” cell lines are transplanted into the spinal cord of SCI mice model, there is initial improvement of motor function, followed by abrupt deterioration secondary to the effect of tumor growth. A significant proportion of the transplanted cells remains undifferentiated after transplantation and is thought to increase the risk of tumorigenesis. In this study, using lentiviral vectors, we introduced the herpes simplex virus type 1 thymidine kinase (HSVtk) gene into a human induced pluripotent stem cell‐derived neural stem/progenitor cell (hiPSC‐NS/PC) line that is known to undergo tumorigenic transformation. Such approach enables selective ablation of the immature proliferating cells and thereby prevents subsequent tumor formation. In vitro, the HSVtk system successfully ablated the immature proliferative neural cells while preserving mature postmitotic neuronal cells. Similar results were observed in vivo following transplantation into the injured spinal cords of immune‐deficient (nonobese diabetic–severe combined immune‐deficient) mice. Ablation of the proliferating cells exerted a protective effect on the motor function which was regained after transplantation, simultaneously defending the spinal cord from the harmful tumor growth. These results suggest a potentially promising role of suicide genes in opposing tumorigenesis during stem cell therapy. This system allows both preventing and treating tumorigenesis following hiPSC‐NS/PC transplantation without sacrificing the improved motor function. Stem Cells Translational Medicine 2019;8:260&270 The herpes simplex virus thymidine kinase (HSVtk) gene was introduced into a tumorigenic cell line of human induced pluripotent stem cell‐derived neural stem/progenitor cells (hiPSC‐NS/PCs) prior to transplantation into spinal cord injury mouse models. Administration of ganciclovir (GCV) following transplantation successfully ablated the immature tumorigenic cells while preserving the mature neuronal cells and the improved motor function.
Tumorigenesis is an important problem that needs to be addressed in the field of human stem/progenitor cell transplantation for the treatment of subacute spinal cord injury (SCI). When certain “tumorigenic” cell lines are transplanted into the spinal cord of SCI mice model, there is initial improvement of motor function, followed by abrupt deterioration secondary to the effect of tumor growth. A significant proportion of the transplanted cells remains undifferentiated after transplantation and is thought to increase the risk of tumorigenesis. In this study, using lentiviral vectors, we introduced the herpes simplex virus type 1 thymidine kinase (HSVtk) gene into a human induced pluripotent stem cell-derived neural stem/progenitor cell (hiPSC-NS/PC) line that is known to undergo tumorigenic transformation. Such approach enables selective ablation of the immature proliferating cells and thereby prevents subsequent tumor formation. In vitro, the HSVtk system successfully ablated the immature proliferative neural cells while preserving mature postmitotic neuronal cells. Similar results were observed in vivo following transplantation into the injured spinal cords of immune-deficient (nonobese diabetic–severe combined immune-deficient) mice. Ablation of the proliferating cells exerted a protective effect on the motor function which was regained after transplantation, simultaneously defending the spinal cord from the harmful tumor growth. These results suggest a potentially promising role of suicide genes in opposing tumorigenesis during stem cell therapy. This system allows both preventing and treating tumorigenesis following hiPSC-NS/PC transplantation without sacrificing the improved motor function. Stem Cells Translational Medicine  2019;8:260&270
Tumorigenesis is an important problem that needs to be addressed in the field of human stem/progenitor cell transplantation for the treatment of subacute spinal cord injury (SCI). When certain “tumorigenic” cell lines are transplanted into the spinal cord of SCI mice model, there is initial improvement of motor function, followed by abrupt deterioration secondary to the effect of tumor growth. A significant proportion of the transplanted cells remains undifferentiated after transplantation and is thought to increase the risk of tumorigenesis. In this study, using lentiviral vectors, we introduced the herpes simplex virus type 1 thymidine kinase (HSVtk) gene into a human induced pluripotent stem cell‐derived neural stem/progenitor cell (hiPSC‐NS/PC) line that is known to undergo tumorigenic transformation. Such approach enables selective ablation of the immature proliferating cells and thereby prevents subsequent tumor formation. In vitro, the HSVtk system successfully ablated the immature proliferative neural cells while preserving mature postmitotic neuronal cells. Similar results were observed in vivo following transplantation into the injured spinal cords of immune‐deficient (nonobese diabetic–severe combined immune‐deficient) mice. Ablation of the proliferating cells exerted a protective effect on the motor function which was regained after transplantation, simultaneously defending the spinal cord from the harmful tumor growth. These results suggest a potentially promising role of suicide genes in opposing tumorigenesis during stem cell therapy. This system allows both preventing and treating tumorigenesis following hiPSC‐NS/PC transplantation without sacrificing the improved motor function. stem cells translational medicine 2019;8:260&270
Tumorigenesis is an important problem that needs to be addressed in the field of human stem/progenitor cell transplantation for the treatment of subacute spinal cord injury (SCI). When certain "tumorigenic" cell lines are transplanted into the spinal cord of SCI mice model, there is initial improvement of motor function, followed by abrupt deterioration secondary to the effect of tumor growth. A significant proportion of the transplanted cells remains undifferentiated after transplantation and is thought to increase the risk of tumorigenesis. In this study, using lentiviral vectors, we introduced the herpes simplex virus type 1 thymidine kinase (HSVtk) gene into a human induced pluripotent stem cell-derived neural stem/progenitor cell (hiPSC-NS/PC) line that is known to undergo tumorigenic transformation. Such approach enables selective ablation of the immature proliferating cells and thereby prevents subsequent tumor formation. In vitro, the HSVtk system successfully ablated the immature proliferative neural cells while preserving mature postmitotic neuronal cells. Similar results were observed in vivo following transplantation into the injured spinal cords of immune-deficient (nonobese diabetic-severe combined immune-deficient) mice. Ablation of the proliferating cells exerted a protective effect on the motor function which was regained after transplantation, simultaneously defending the spinal cord from the harmful tumor growth. These results suggest a potentially promising role of suicide genes in opposing tumorigenesis during stem cell therapy. This system allows both preventing and treating tumorigenesis following hiPSC-NS/PC transplantation without sacrificing the improved motor function. Stem Cells Translational Medicine 2019;8:260&270.Tumorigenesis is an important problem that needs to be addressed in the field of human stem/progenitor cell transplantation for the treatment of subacute spinal cord injury (SCI). When certain "tumorigenic" cell lines are transplanted into the spinal cord of SCI mice model, there is initial improvement of motor function, followed by abrupt deterioration secondary to the effect of tumor growth. A significant proportion of the transplanted cells remains undifferentiated after transplantation and is thought to increase the risk of tumorigenesis. In this study, using lentiviral vectors, we introduced the herpes simplex virus type 1 thymidine kinase (HSVtk) gene into a human induced pluripotent stem cell-derived neural stem/progenitor cell (hiPSC-NS/PC) line that is known to undergo tumorigenic transformation. Such approach enables selective ablation of the immature proliferating cells and thereby prevents subsequent tumor formation. In vitro, the HSVtk system successfully ablated the immature proliferative neural cells while preserving mature postmitotic neuronal cells. Similar results were observed in vivo following transplantation into the injured spinal cords of immune-deficient (nonobese diabetic-severe combined immune-deficient) mice. Ablation of the proliferating cells exerted a protective effect on the motor function which was regained after transplantation, simultaneously defending the spinal cord from the harmful tumor growth. These results suggest a potentially promising role of suicide genes in opposing tumorigenesis during stem cell therapy. This system allows both preventing and treating tumorigenesis following hiPSC-NS/PC transplantation without sacrificing the improved motor function. Stem Cells Translational Medicine 2019;8:260&270.
Audience Academic
Author Nagoshi, Narihito
Miyoshi, Hiroyuki
Sugai, Keiko
Fukuzawa, Ryuji
Shibata, Shinsuke
Matsumoto, Morio
Ozaki, Masahiro
Kawabata, Soya
Iida, Tsuyoshi
Kohyama, Jun
Yasutake, Kaori
Renault‐Mihara, Francois
Nakamura, Masaya
Kojima, Kota
Itakura, Go
Ito, Shuhei
Okano, Hideyuki
AuthorAffiliation 2 Department of Orthopaedic Surgery Keio University School of Medicine Tokyo Japan
1 Department of Physiology Keio University School of Medicine Tokyo Japan
3 Department of Pathology International University of Health and Welfare Chiba Japan
AuthorAffiliation_xml – name: 3 Department of Pathology International University of Health and Welfare Chiba Japan
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/30485733$$D View this record in MEDLINE/PubMed
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Issue 3
Keywords Human induced pluripotent stem cell-derived neural stem/progenitor cell
Stem cell therapy
Spinal cord injury
Suicide gene
Herpes simplex virus thymidine kinase
Language English
License Attribution-NonCommercial-NoDerivs
2018 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.
http://creativecommons.org/licenses/by-nc-nd/4.0
This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
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content type line 23
Contributed equally.
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Snippet Tumorigenesis is an important problem that needs to be addressed in the field of human stem/progenitor cell transplantation for the treatment of subacute...
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SubjectTerms Ablation
Animals
Apoptosis
Carcinogenesis - pathology
Cell cycle
Cell Differentiation - physiology
Cells, Cultured
Cytotoxicity
Diabetes mellitus
Disease Models, Animal
Enabling Technologies for Cell‐Based Clinical Translation
Female
Genes
Herpes simplex
Herpes simplex virus thymidine kinase
Herpes viruses
Human induced pluripotent stem cell‐derived neural stem/progenitor cell
Humans
Induced Pluripotent Stem Cells - cytology
Medical research
Mice
Mice, Inbred NOD
Mice, SCID
Neural stem cells
Neural Stem Cells - cytology
Neurons - physiology
Pharmaceutical industry
Pluripotency
Progenitor cells
Recovery of Function - physiology
Scientific equipment and supplies industry
Spinal Cord - physiology
Spinal cord injuries
Spinal Cord Injuries - therapy
Spinal cord injury
Stem cell research
Stem cell therapy
Stem cell transplantation
Stem Cell Transplantation - methods
Stem cells
Suicide
Suicide gene
Suicide genes
Tetracycline
Tetracyclines
Thymidine
Thymidine kinase
Transplantation
Tumorigenesis
Tumors
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Title Selective Ablation of Tumorigenic Cells Following Human Induced Pluripotent Stem Cell‐Derived Neural Stem/Progenitor Cell Transplantation in Spinal Cord Injury
URI https://onlinelibrary.wiley.com/doi/abs/10.1002%2Fsctm.18-0096
https://www.ncbi.nlm.nih.gov/pubmed/30485733
https://www.proquest.com/docview/2331419489
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https://pubmed.ncbi.nlm.nih.gov/PMC6392358
Volume 8
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